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SR-Mitochondria Crosstalk Shapes Ca Signalling to Impact Pathophenotype in Disease Models Marked by Dysregulated

Brian D Tow1, Arpita Deb1, Shraddha Neupane1

  • 1Department of Biological Sciences, Mississippi State University, 295 Lee Blvd, Starkville, Mississippi, 39762, USA.

Cardiovascular Research
|October 22, 2021
PubMed

Insights

Mitochondria play distinct roles in cardiac diseases by buffering or exacerbating calcium release, influencing disease progression and arrhythmias differently in CPVT2 and pre-diabetic models.

Area of Science:

  • Cardiology
  • Mitochondrial Biology
  • Calcium Signaling

Background:

  • Diastolic calcium release (DCR) from the sarcoplasmic reticulum (SR) via ryanodine receptor 2 (RyR2) is implicated in cardiac pathologies.
  • The precise role of SR-mitochondria interplay in shaping diverse cardiac disease phenotypes remains unclear.

Purpose of the Study:

  • To investigate how the interplay between SR and mitochondria influences calcium (Ca) signaling in distinct cardiac pathologies.
  • To elucidate the differential roles of mitochondrial calcium handling in catecholaminergic polymorphic ventricular tachycardia (CPVT2) and pre-diabetic cardiomyopathy (FFD).

Main Methods:

  • Utilized a genetic CPVT2 model (CASQ2 knockout) and a fructose-fed mice (FFD) model exhibiting DCR.
  • Modulated mitochondrial calcium (mCa) by targeting the mitochondrial calcium uniporter (MCU) and mitochondrial permeability transition pore (mPTP).
  • Assessed Ca waves, mitochondrial Ca content, mitochondrial reactive oxygen species (mtROS), and arrhythmias.

Main Results:

  • MCU activation abolished Ca waves in CPVT2 but worsened them in FFD, highlighting mitochondria's dual role as Ca buffer or mtROS source.
  • Enhanced mCa uptake reduced mtROS in CPVT2 but increased it in FFD.
  • CPVT2 mitochondria utilized mPTP-mediated Ca efflux to prevent overload, unlike FFD.
  • Inhibition of mPTP exacerbated arrhythmias in CPVT2.

Conclusions:

  • Mitochondria buffer SR-derived DCR in CPVT2 to mitigate pathological remodeling, relying on mPTP efflux to prevent overload.
  • FFD is more susceptible to mtROS-dependent RyR2 leak.
  • The SR-mitochondria interplay distinctly shapes intracellular Ca signaling, contributing to divergent cardiac pathologies.
Abstract

Keywords:
CPVTCalcium signallingEC-couplingRyR2

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